First pharmacophore-based identification of androgen receptor down-regulating agents: Discovery of potent anti-prostate cancer agents

Abstract

A qualitative 3D pharmacophore model (a common feature based model or Catalyst HipHop algorithm) was developed for well-known natural product androgen receptor down-regulating agents (ARDAs). The four common chemical features identified included: one hydrophobic group, one ring aromatic group, and two hydrogen bond acceptors. This model served as a template in virtual screening of the Maybridge and NCI databases that resulted in identification of six new ARDAs (EC(50) values 17.5-212 microM). Five of these molecules strongly inhibited the growth of human prostate LNCaP cells. These novel compounds may be used as leads to develop other novel anti-prostate cancer agents.

Combination Therapy of Antiandrogen and XIAP Inhibitor for Treating Advanced Prostate Cancer

“…Purushottamachar et al provided clear evidence concerning structural requirements common to ARDAs (24). Typical features include one hydrophobic group, one aromatic group, and two hydrogen bond acceptors (24). Both embelin and embelin-6g satisfy these structural criteria and hence it may not be surprising that they are capable of depleting AR expression.…”

“…Examples of these AR down-regulating agents (ARDA) include quercetin, epicatechin, and curcumin. Purushottamachar et al provided clear evidence concerning structural requirements common to ARDAs (24). Typical features include one hydrophobic group, one aromatic group, and two hydrogen bond acceptors (24).…”

Exploring Novel Target Space: A Need to Partner High Throughput Docking and Ligand-Based Similarity Searches?

“…In another recent example Purushottamachar et al [142] reported the discovery of several potent Prostate cancer (PCa) inhibitors that function analogous to androgen receptor (AR) down regulating agents or ARDAs. ARDAs prevent the development, progression and proliferation of PCa by selectively targeting and inhibiting the AR through a mechanism that decreases its expression and thus function.…”

“…These novel compounds were identified on the basis of a 3D-pharmacophore model of 5 known ARDAs belonging to the class of dietary compounds (natural products) via 3D-database searching of NCI and Maybridge databases using a functional descriptor based pharmacophore model (Fig. 6c) that was generated using the HipHop algorithm of Catalyst4.10 [142]. This pharmacophore model contains four features: one hydrophobic group (which is permitted be an aromatic or aliphatic moiety), one ring aromatic group and two hydrogen bond acceptor groups (Fig.…”

Human Androgen Receptor Inhibitors: Computational 3D QSAR Studies to Design Lead Compounds for Treatment of Prostate Cancer

“…Indeed, the AR is expressed in all histological types and stages of PCA, including hormone refractory tumors. With this knowledge, it is reasonable to suggest that effective strategies (investigational new drugs) that lead to AR down-regulation and/or AR modulation may be useful for preventing the development, progression and treatment of PCA [5]. The three dimensional quantitative structure activity relationships (3D-QSAR) may be useful in drug discovery and design [6].…”